期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 17, 期 2, 页码 634-640出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.11.064
关键词
Hsp90; Cancer; Naphthoquinone; MCF-7; Anti-proliferation; High-throughput screening
资金
- National Institutes of Health [NIH-1R01CA125392]
- OAES project 1975
- Kansas Cancer Center
- KINBRE Scholarship
High-throughput screening of a library of diverse molecules has identified the 1,4-naphthoquinone scaffold as a new class of Hsp90 inhibitors. The synthesis and evaluation of a rationally-designed series of analogues containing the naphthoquinone core scaffold has provided key structure-activity relationships for these compounds. The most active inhibitors exhibited potent in vitro activity with low micromolar IC50 values in anti-proliferation and Her2 degradation assays. In addition, 3g, 12, and 13a induced the degradation of oncogenic Hsp90 client proteins, a hallmark of Hsp90 inhibition. The identification of these naphthoquinones as Hsp90 inhibitors provides a new scaffold upon which improved Hsp90 inhibitors can be developed. (C) 2008 Elsevier Ltd. All rights reserved.
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